The long-term goal of this project is to elucidate how inter- and intra-neuronal signaling contributes to neuronal development and function. Interneuronal communication occurs at synapses; disruption of synapse formation and function in developing and adult humans causes myriad neurological and psychiatric disorders, including schizophrenia, bipolar disease, and learning disabilities. The goal of the studies proposed here is to investigate the biological role of the PDZ domain protein NIL-16 in the nervous system. NIL-16 is uniquely bifunctional, serving both as a specific ion channel binding molecule and as the neuron-specific precursor of the cytokine, interleukin (IL)- 16. Until NIL- 16 was cloned, IL16 had been characterized only in the immune system. The identification of NIL-16 revealed an unsuspected parallel between the immune and nervous systems. IL-16 induces a signaling cascade in neurons that leads to upregulation of the transcription factor Fos. Therefore, NIL- 16 represents the first molecular link between cytokine signaling and ion channel function. Remarkably, preliminary studies revealed that NIL-16 can bind CD4, a functional IL- 16 receptor in the immune system. These findings suggest that NIL- 16 may function as both the precursor of IL- 16 and the molecular anchor for its receptor. Moreover, because NIL- 16 also binds ion channels, IL- 16 signaling may ultimately modulate the function of ion channels. These studies have three specific aims: 1) To test the hypothesis that NIL-16 serves as a scaffolding or trafficking protein that influences ion channel function by using electrophysiological recordings, immunoprecipitation, immunofluorescence confocal microscopy, and endocytosis assays; 2) To test the hypothesis that there is a specific IL-16 signaling pathway in neurons by studies in mutant mice, chemical cross-linking studies, kinase and phosphorylation assays, subcellular localization studies, and electrophysiological recordings; and 3) To test the hypothesis that NIL-16 influences long-term potentiation (LTP) by comparative electrophysiological recordings from brain tissue of wild-type and NIL-16-deficient mice.